Quinolones share a common interaction domain on topoisomerase II with other DNA cleavage-enhancing antineoplastic drugs
Quinolones share a common interaction domain on topoisomerase II with other DNA cleavage-enhancing antineoplastic drugs
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DOI：
10.1021/bi962488f
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发表时间：
1997-03-11
期刊：
影响因子：
2.9
通讯作者：
Osheroff, N
中科院分区：
文献类型：
--
作者：
Elsea, SH;Westergaard, M;Osheroff, N
拓扑异构酶 II 是许多临床相关抗肿瘤药物的细胞毒性靶点。尽管这些药物在结构上存在显着差异，但先前的一项研究 [Corbett, A. H., Hong, D., & Osheroff, N. (1993) J. Biol.化学。 268, 14394-14398]表明依托泊苷对拓扑异构酶 II 的作用位点与其他 DNA 裂解增强药物的作用位点重叠。因此，为了进一步定义药物和酶之间的相互作用，针对几类抗肿瘤药物绘制了果蝇拓扑异构酶 Ii 上喹诺酮类药物的功能相互作用域（即由药物功能定义的相互作用域）。这是通过表征环丙沙星（一种旋转酶靶向抗菌喹诺酮）对依托泊苷、安吖啶、染料木黄酮和抗肿瘤喹诺酮 CP-115,953 增强拓扑异构酶 II 介导的 DNA 切割能力的影响来完成的。尽管环丙沙星与真核 II 型酶相互作用，但它几乎没有刺激 DNA 裂解的能力。环丙沙星减弱了所有上述药物的裂解增强作用。使用相关的喹诺酮 CP-80,080 作为竞争对手，也获得了类似的结果。此外，DNA 裂解的动力学分析表明环丙沙星是 CP-115,953 和依托泊苷的竞争性抑制剂。最后，环丙沙星在哺乳动物细胞中抑制 CP-115,953 和依托泊苷的细胞毒性作用，其程度与其体外裂解减弱程度相当。这些结果强烈表明，几种结构不同的 DNA 切割增强抗肿瘤药物对拓扑异构酶 II 具有重叠的作用位点。基于药物竞争和诱变研究的结果，描述了拓扑异构酶 II 上药物相互作用域的模型。
Topoisomerase II is the cytotoxic target for a number of clinically relevant antineoplastic drugs. Despite the fact that these agents differ significantly in structure, a previous study [Corbett, A. H., Hong, D., & Osheroff, N. (1993) J. Biol. Chem. 268, 14394-14398] indicated that the site of action for etoposide on topoisomerase II overlaps those of other DNA cleavage-enhancing drugs. Therefore, to further define interactions between drugs and the enzyme, the functional interaction domain (i.e., interaction domain defined by drug function) for quinolones on Drosophila topoisomerase Ii was mapped with respect to several classes of antineoplastic agents. This was accomplished by characterizing the effects of ciprofloxacin (a gyrase-targeted antibacterial quinolone) on the ability of etoposide, amsacrine, genistein, and the antineoplastic quinolone, CP-115,953, to enhance topoisomerase II-mediated DNA cleavage. Although ciprofloxacin interacts with the eukaryotic type II enzyme, it shows little ability to stimulate DNA cleavage. Ciprofloxacin attenuated cleavage enhancement by all of the above drugs. Similar results were obtained using a related quinolone, CP-80,080, as a competitor. In addition, kinetic analysis of DNA cleavage indicated that ciprofloxacin is a competitive inhibitor of CP-115,953 and etoposide. Finally, ciprofloxacin inhibited the cytotoxic actions of CP-115,953 and etoposide in mammalian cells to an extent that paralleled its in vitro attenuation of cleavage. These results strongly suggest that several structurally disparate DNA cleavage-enhancing antineoplastic drugs share an overlapping site of action on topoisomerase II. Based on the results of drug competition and mutagenesis studies, a model for the drug interaction domain on topoisomerase II is described.